Ravoori Srivani, Vadhanam Manicka V, Davey Diane D, Srinivasan Cidambi, Nagarajan Bala, Gupta Ramesh C
James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Int J Oncol. 2006 Dec;29(6):1437-43.
Progressive accumulation of DNA lesions leads to genetic mutations that are central to the process of tumorigenesis. Human cervix provides an ideal system to determine progressive accumulation of DNA adducts in the target tissue because of its accessibility during routine diagnostic checkups. Uterine cervix samples from various pathologies, i.e. normal (n=13), inflammation (n=9), dysplasia (n=5) and different stages of invasive cancer (n=47), were analyzed for DNA adduct burden by modified 32P-postlabeling/TLC systems. Six subgroups of adducts were detected in the following descending order of polarities: P-1, P-2, PL-1, PL-2, L-1 and L-2 (P, polar; L, lipophilic; PL, between polar and lipophilic). No qualitative differences were observed in adduct profiles in the various cervix pathologies analyzed. However, significant quantitative differences were found. Previously known lipophilic adducts increased significantly from normal to cancer (144+/-61 to 503+/-51 adducts/10(9) nucleotides). Interestingly, the newly discovered polar adducts were present at 61- to 527-fold higher levels than lipophilic adducts. Of all the polar adducts, the known mutagenic lesion, 8-oxodeoxyguanosine, predominated in all cervix conditions. Notably, this lesion was elevated 27-fold in inflammation compared with normal cervix (51,058+/-9,863 versus 1,886+/-507 adducts/10(9) nucleotides). The P-1, PL-1, PL-2 and L-1 adducts were elevated 3- to 13-fold in inflammation compared with normal cervix, and were also higher in dysplasia and cancer. Our data suggest that inflammation may be involved in directing the course of disease progression by accumulating higher levels of DNA lesions. The data further suggest the biomarker potential of the newly detected array of DNA adducts.
DNA损伤的逐步积累会导致基因突变，而基因突变是肿瘤发生过程的核心。由于在常规诊断检查中易于获取，人类子宫颈为确定目标组织中DNA加合物的逐步积累提供了一个理想的系统。通过改良的32P后标记/TLC系统，对来自各种病理状态的子宫颈样本进行分析，这些病理状态包括正常（n = 13）、炎症（n = 9）、发育异常（n = 5）和不同阶段的浸润性癌（n = 47），以检测DNA加合物负荷。检测到六个加合物亚组，极性由高到低依次为：P-1、P-2、PL-1、PL-2、L-1和L-2（P，极性；L，亲脂性；PL，介于极性和亲脂性之间）。在所分析的各种子宫颈病理状态中，加合物谱未观察到定性差异。然而，发现了显著的定量差异。先前已知的亲脂性加合物从正常到癌症显著增加（144±61至503±51个加合物/10⁹核苷酸）。有趣的是，新发现的极性加合物的水平比亲脂性加合物高61至527倍。在所有极性加合物中，已知具有诱变作用的损伤8-氧代脱氧鸟苷在所有子宫颈状态中占主导地位。值得注意的是，与正常子宫颈相比，该损伤在炎症中升高了27倍（51,058±9,863与1,886±507个加合物/10⁹核苷酸）。与正常子宫颈相比，P-1、PL-1、PL-2和L-1加合物在炎症中升高了3至13倍，在发育异常和癌症中也更高。我们的数据表明，炎症可能通过积累更高水平的DNA损伤参与指导疾病进展过程。数据进一步表明新检测到的一系列DNA加合物具有作为生物标志物的潜力。
